Project Summary/Abstract Peripheral artery disease (PAD) is a major cause of morbidity and mortality however few effective therapies exist. Treatment is limited to surgical or percutaneous revascularization, which provides modest benefit without improving long-term outcomes. PAD may present as either intermittent claudication (IC), with exertion-induced pain, or as critical limb ischemia (CLI), defined by rest pain or tissue necrosis. While CLI was historically believed to represent the natural progression from IC in patients with PAD, CLI and IC are now understood to be distinct phenotypic manifestations of PAD driven by genetic susceptibility to ischemic tissue necrosis. Identifying factors that predispose to the development of CLI will be critical to reducing morbidity, mortality, and health care costs however the specific mechanisms that underlie susceptibility to tissue necrosis remain unclear. The long-term goal of our research is to determine the mechanisms by which CLI develops and to identify potential therapeutic targets for this disease. The objective of this proposal is to characterize the mechanism by which endogenous muscle progenitor cells provide an adaptive response to ischemia and limit tissue necrosis. While the vast majority of studies investigating PAD focus on the contribution of the vasculature to this process, our lab has demonstrated that skeletal muscle, and endogenous muscle progenitor cells (MPCs) in particular, serves as a key determinant in the development of tissue necrosis in response to limb ischemia. Preliminary studies using a murine model of subacute hind limb ischemia (HLI) have suggested that ablation of MPCs results in severe tissue necrosis even in typically necrosis-resistant strains of mice and that MPCs incorporate into new blood vessels in response to ischemia. Taken together, these findings suggest a model in which MPCs incorporate into neovessels in order to support tissue perfusion while also directly contributing to muscle regeneration. The central hypothesis of this proposal is that endogenous muscle progenitor cells mediate both skeletal muscle neovascularization and myofiber regeneration in response to ischemia. The specific aims of this proposal are: 1. Define the role of MPCs in skeletal muscle myofiber regeneration and neovascularization in response to ischemia 2. Characterize the number and function of MPCs in patients with CLI and IC These experiments will improve our understanding of the mechanisms by which vascular disease develops and provide novel therapeutic targets. Moreover, the skills I will acquire during this fellowship will help to establish me as an independent investigator and a surgeon-scientist focused on the development of translational PAD therapies.